Impact of HSV-1 Infection on Alzheimer’s Disease Neurodegeneration Markers: Insights from LUHMES 2D and 3D Neuronal Models

TL;DR

This study shows that HSV-1 infection in human neuronal models causes Alzheimer’s-like changes, including amyloid and tau buildup and disrupted cell waste systems.

Contribution

The study demonstrates HSV-1-induced AD-like neuropathology in a novel 3D LUHMES neuronal model system.

Findings

HSV-1 infection causes intracellular accumulation of beta-amyloid peptides and tau hyperphosphorylation in LUHMES neurons.

HSV-1 disrupts the autophagy–lysosome pathway, with increased LC3-II and reduced cathepsin activity.

3D LUHMES neuronal aggregates show AD-like alterations and susceptibility to HSV-1 infection.

Abstract

Herpes simplex virus type 1 (HSV-1) has been proposed as an environmental risk factor for Alzheimer’s disease (AD). Viral infection of neuronal cells can reproduce hallmark pathological features of AD, including intracellular beta-amyloid (Aβ) accumulation, tau hyperphosphorylation, and lysosomal dysfunction. However, the molecular mechanisms underlying these alterations remain unclear, partly due to limitations of existing experimental models. Here, we established both two-dimensional (2D) and three-dimensional (3D) LUHMES neuronal cultures—a human mesencephalic-derived neural cell line that differentiates rapidly into mature neurons—to investigate HSV-1-induced AD-associated markers. Our results demonstrate that HSV-1 infection induces key features of AD, including intracellular accumulation of Aβ peptides and hyperphosphorylation of tau protein. Moreover, we observed disruptions in the autophagy–lysosome pathway, characterized by increased LC3-II levels, reduced cathepsin activity, and impaired lysosomal burden. Notably, these AD-like alterations were reproduced in 3D LUHMES neuronal aggregates, confirming their susceptibility to productive HSV-1 infection. Collectively, these findings indicate that HSV-1 not only triggers AD-like neuropathological markers but also disrupts cellular clearance mechanisms that may contribute to neuronal dysfunction and degeneration. This study validates the 3D LUHMES system as a useful human neuronal model to study virus-induced neurodegeneration and its mechanistic links to AD pathology.

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